The Neuroimmune Semaphorin-3A Reduces Inflammation and Progression of Experimental Autoimmune Arthritis
The Neuroimmune Semaphorin-3A Reduces Inflammation and Progression of Experimental Autoimmune Arthritis
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DOI：
10.4049/jimmunol.0903527
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发表时间：
2010-11-15
影响因子：
4.4
通讯作者：
Catalano, Alfonso
中科院分区：
文献类型：
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作者：
Catalano, Alfonso
Semaphorin-3A (Sema3A) 是一个保守蛋白大家族的成员，最初与轴突引导有关，由活化的 T 细胞表达，并在体外下调 T 细胞活化。本研究探讨了 Sema3A 过度表达在胶原诱导关节炎小鼠模型中的作用和机制。预防性腹腔注射与没有插入片段的对照质粒相比，给予编码 Sema3A 的质粒 DNA 显着降低了发病率、疾病严重程度和关节炎症。 Sema3A 的治疗降低了抗胶原 IgG 水平并抑制了胶原特异性促炎细胞因子（IFN-γ 和 IL-17）的释放，但增加了血清中 IL-10 的浓度。与关节炎小鼠的结果一致，来自类风湿性关节炎患者的 CD4(+) T 细胞中的 Sema3A 表达存在缺陷。相反，在相同细胞中检测到 Sema3A 受体神经毡蛋白-1 (NP-1) 的表达增加。 CD4(+) NP-1(+) T 细胞是参与免疫反应控制的 T 细胞亚群。它们表达大量的 IL-10，并对自体 CD4(+) T 细胞表现出抑制活性。 Sema3A直接作用于CD4(+) NP-1(+) T细胞，因为它可以增加IL-10的产生并影响CD4(+) T细胞生长的调节功能。因此，我认为Sema3A增加了CD4(+) NP-1(+) T细胞抑制同种异体反应的能力，其瞬时表达在类风湿性炎症中发生改变，并且重新引入Sema3A足以减轻胶原诱导的关节炎，支持其在治疗自身免疫性疾病中的治疗潜力。免疫学杂志，2010，185：6373-6383。
Semaphorin-3A (Sema3A), a member of a large family of conserved proteins originally implicated in axon guidance, is expressed by activated T cells and downmodulates T cell activation in vitro. This study examined the effect and mechanism of action of Sema3A overexpression in a mouse model of collagen-induced arthritis. Prophylactic i.p. administration of plasmid DNA encoding Sema3A markedly reduced the incidence, disease severity, and articular inflammation compared with control plasmid without insert. Treatment of Sema3A reduced anticollagen IgG levels and suppressed collagen-specific proinflammatory cytokine (IFN-gamma and IL-17) release, but increased IL-10 concentration in the serum. In line with results in arthritic mice, Sema3A expression is defective in CD4(+) T cells derived from patients with rheumatoid arthritis. In contrast, increased expression of the Sema3A receptor neuropilin-1 (NP-1) is detected in the same cells. The CD4(+) NP-1(+) T cells are a T cell subset involved in the control of the immune responses. They express greater amounts of IL-10 and show suppressive activities on autologous CD4(+) T cells. Sema3A acted directly on CD4(+) NP-1(+) T cells, because it could increase IL-10 production and influence the regulatory function on CD4(+) T cell growth. Therefore, I propose that Sema3A increases the CD4(+) NP-1(+) T cell ability to suppress alloresponses, that its transient expression is altered in rheumatoid inflammation, and that reintroduction of Sema3A is sufficient to attenuate collagen-induced arthritis, supporting its therapeutic potential in the treatment of autoimmune disorders. The Journal of Immunology, 2010, 185: 6373-6383.